Infertility drugs increase the risk of ovarian cancer--new study shows.

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A higher rate of ovarian cancer has been found among women who took infertility drugs (The New England Journal of Medicine, 22 September 1994). The finding validates a concern about these drugs that surfaces periodically in medical journals. The study is bound to generate strong criticism from the infertility industry, now a $1 billion-a-year profit-making enterprise.

The medical records of 3,837 women who underwent infertility treatment between 1974 and 1985 in Seattle, were analyzed by Mary Anne Rossing, D.V.M., Ph.D., and colleagues at the University of Washington and the Fred Hutchinson Cancer Research Center. Most of the women had taken Clomid, a drug which induces ovulation. There were 11 cases of ovarian cancer diagnosed within the study period; nine of these women had taken Clomid and five of the nine had taken the drug during 12 or more monthly cycles. Normally, about four cases of ovarian cancer would be expected in a similar cohort of infertile women who did not take infertility drugs.

A review of 12 studies made national headlines over a year ago because it showed an increased risk of ovarian cancer among women who took infertility drugs but didn't become pregnant. The Seattle study, on the other hand, shows the increased risk of ovarian cancer is present whether or not the woman becomes pregnant.

Drug therapy, rather than any preexisting ovulatory abnormality, appears to be responsible for the development of cancer. The elevated ovarian cancer risk is shown both in women with ovarian abnormalities and in those with well-functioning ovaries, although the risk was twice as high among the treated women with ovulatory abnormalities.

The new study also indicates widespread inappropriate use of Clomid. There is no scientific evidence to show that this drug can benefit women without ovulatory dysfunction, yet medical records show that 52% of the infertile women who took Clomid in the Seattle study had normally functioning ovaries. The practice stems from the "misguided notion that if [Clomid] makes a subfertile woman more fertile, then surely it can only make a normal woman more fertile," according to Robert Nachtigall, M.D., and Elizabeth Mehren, authors of Overcoming Infertility (New York: Doubleday, 1991).

Given the fact that the Seattle study period ended in the mid-1980s, some significant information gaps remain about the safety of infertility drugs. For example, few women in the study had taken more powerful drugs like Pergonal and Lupron, which are standard protocol for in vitro fertilization (IVF). Given in higher doses for IVF, these drugs stimulate the release of multiple eggs which are removed from the ovaries of the infertile women and fertilized with the husband's sperm in the laboratory ("test tube babies"). The fertilized eggs are allowed to incubate before they are placed in the woman's uterus two days later. IVF has grown in popularity in the last decade, though studies show that the procedure benefits only women with tube abnormalities.

Drug-Treated Donors
When drugs fail to produce normal ovulation, infertile women can undergo IVF with donor eggs. "The Seattle study raises concerns about the women who take these drugs in order to be egg donors," said Ann Pappert, an investigative reporter currently working on a book about the infertility industry. "For a long time, there have been warnings from some members of the medical community because these drugs are not intended for women with a normally functioning reproductive system. But you are not chosen to be a donor unless you have a particularly well functioning reproductive system," observes Pappert, who says that she interviewed women who have been donors 12 or 14 times. The women are paid $1,500 and upwards.

In an editorial that accompanied the Seattle study, Alice S. Whittemore, Ph.D., of Stanford University School of Medicine, called for perspective on the magnitude of the cancer risk associated with infertility drugs. "If ovulation-stimulating drugs cause ovarian cancer, the risk is two to three times that in the general population. But ovarian cancer is a rare disease; the lifetime risk for U.S. is about 1.8%. These estimates suggest a lifetime risk of at most approximately 4 to 5% among women exposed to fertility medications... [which] should be balanced against the physical and psychological benefits of pregnancy."

It's interesting to note that ovarian cancer becomes a rare disease when doctors want to downplay a drug side effect, yet it is often described as the leading cause of death from gynecologic malignancies in the U.S., particularly by doctors advocating preventive removal of healthy ovaries during hysterectomy. Dr. Whittemore concedes that the benefits of pregnancy do not apply to women who take fertility drugs to serve as egg donors.

The true extent of fertility drug-caused ovarian cancer will not be known for many more years. The average age of the women at the end of the Seattle study period was the early forties, whereas ovarian cancer is overwhelmingly a disease of older women.

"Clomid has been on the market for 27 years, and they should have been asking about the long-term risks years earlier," said Ann Pappert. "We don't know anything about the long-term risks of other infertility drugs like Pergonal and Lupron, which are more powerful and more commonly used today. The Seattle investigators say they found no ovarian cancer link to Pergonal, but only 25 women in their study had taken the drug."

Thanks to funding from the National Institutes of Health, the Seattle study will be expanded and the women will continue to be followed. But, in Ann Pappert's opinion, the move is long overdue and not expansive enough. "There has been no long-term followup of women treated for infertility, their children, or the women who take the drugs in order to serve as donors."

Physicians and the pharmaceutical industry are making huge profits treating infertility, and hyperstimulation drugs are central to their limited success in producing healthy infants. A powerful incentive exists to overlook or downplay any bad news.

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